PROJECT SUMMARY Clinically Isolated Syndrome (CIS) patients experiencing their first neurological clinical episode related to Central Nervous System (CNS) inflammation represent a unique opportunity to study the earliest immunological events associated with CNS inflammation prior to treatment initiation. Our laboratory has acquired the largest human sample repository of CIS patients experiencing their first clinical episode. Our preliminary data using state-of- the-art cellular and genetic phenotyping demonstrate extensive B cell dysregulation within our untreated, CIS cohort compared to controls including an expanded population of a B cell subtype called CD27high plasmablasts in the cerebrospinal fluid (CSF) and peripheral blood at the time of their first documented clinical attack. In fact, those patients with CD27high plasmablast expansion at the time of their first clinical attack were the only ones who had documented exacerbations over the next two years. In addition, circulating CD27high plasmablasts utilizing particular antibody genes tend to produce antibodies that bind neuronal antigens. These findings have prompted us to question whether CD27high plasmablasts are involved in the autoreactivity associated with this subset of CIS patients at high risk to convert to MS at the time of their first documented clinical attack. We are also investigating whether Radiologically Isolated Syndrome (RIS) patients, who display CNS inflammation similar to CIS patients but without clinical symptoms also exhibit expansion of CD27high plasmablasts that produce anti-neuronal antibodies. The focus of this project will facilitate new mechanistic insights into the contribution of CD27high plasmablasts in early CNS inflammation.